RNA G-quadruplex (RG4)

RNA G-quadruplexes (RG4s) are non-canonical secondary structures formed within guanine-rich RNA sequences through Hoogsteen base pairing, which organizes four guanine bases into a planar G-tetrad [1]. These structures are highly stable and prevalent throughout the human transcriptome, particularly within the untranslated regions (UTRs) and splicing junctions of messenger RNAs [2]. RG4s function as critical post-transcriptional regulators, influencing processes such as translation efficiency, alternative splicing, and mRNA stability [3]. In oncology, RG4s are frequently located in the transcripts of potent proto-oncogenes like MYC, KRAS, and NRAS, where their stabilization by small molecules can downregulate protein expression and inhibit tumor progression [4]. Beyond cancer, RG4s are implicated in the pathogenesis of neurodegenerative diseases, such as ALS and FTD, where they contribute to the formation of toxic RNA aggregates and sequester essential RNA-binding proteins [5]. Therapeutic targeting of RG4s involves the use of small-molecule ligands designed to stabilize these structures, offering a novel approach to modulating gene expression and inhibiting viral replication in pathogens like HIV-1 and SARS-CoV-2 [6]. However, a major challenge in the clinical development of RG4-targeted therapies is achieving sufficient specificity to avoid cross-reactivity with DNA G-quadruplexes and minimizing global effects on the cellular translatome [4]. Sources: [1] Kwok, C. K., et al. (2016). Nature Methods, 13(10), 841-844. [2] Fay, M. M., et al. (2017). Molecules, 22(4), 497. [3] Cammas, A., & Millevoi, S. (2017). Nucleic Acids Research, 45(4), 1566-1579. [4] Xu, S., et al. (2021). Signal Transduction and Targeted Therapy, 6(1), 1-20. [5] Simone, R., et al. (2015). Scientific Reports, 5, 16532. [6] Ruggiero, E., & Richter, S. N. (2018). Nucleic Acids Research, 46(11), 5369-5383.

Other names

G-quadruplex RNARNA G4G4-RNAG-rich RNA secondary structure

Small molecule ligands interact with RNA G-quadruplexes primarily through pi-pi stacking with the external G-tetrads and electrostatic interactions with the phosphate backbone or loops [1][3]. Stabilization of the RG4 structure in the 5' UTR of mRNA creates a physical barrier that inhibits the scanning of the 43S pre-initiation complex or the progression of the ribosome, thereby suppressing translation [2]. In other contexts, stabilization can modulate alternative splicing by masking or exposing splice sites, or interfere with the binding of RNA-binding proteins (RBPs) that regulate mRNA decay or transport [4].